Proton Pump Inhibitor Use May Not Prevent High-grade Dysplasia and Oesophageal Adenocarcinoma in Barrett's Oesophagus

A Nationwide Study of 9883 Patients

F. Hvid-Jensen; L. Pedersen; P. Funch-Jensen; A. M. Drewes

Disclosures

Aliment Pharmacol Ther. 2014;39(9):984-991. 

In This Article

Abstract and Introduction

Abstract

Background: Proton pump inhibitors (PPI) may potentially modify and decrease the risk for development of oesophageal adenocarcinoma in Barrett's oesophagus (BO).

Aim: To investigate if the intensity and adherence of PPI use among all patients with BO in Denmark affected the risk of oesophageal adenocarcinoma.

Methods: We performed a nationwide case–control study in Denmark among 9883 patients with a new diagnosis of BO. All incident oesophageal adenocarcinomas and high-grade dysplasias were identified, and risk ratios were estimated on the basis of prior use of PPIs. Sex- and age-matched BO patients without dysplasia or malignancies in a 10:1 ratio were used for comparison. Conditional logistic regression was used for analysis, adjusting for low-grade dysplasia, gender and medication.

Results: We identified 140 cases with incident oesophageal adenocarcinomas and/or high-grade dysplasia, with a median follow-up time of 10.2 years. The relative risk of oesophageal adenocarcinoma or high-grade dysplasia was 2.2 (0.7–6.7) and 3.4 (95% CI: 1.1–10.5) in long-term low- and high-adherence PPI users respectively.

Conclusions: No cancer-protective effects from PPI's were seen. In fact, high-adherence and long-term use of PPI were associated with a significantly increased risk of adenocarcinoma or high-grade dysplasia. This could partly be due to confounding by indication or a true negative effect from PPIs. Until the results from future studies hopefully can elucidate the association further, continuous PPI therapy should be directed at symptom control and additional modalities considered as aid or replacement.

Introduction

Barrett's oesophagus (BO) and its connection to gastro-oesophageal reflux was described by Normann Barrett in the early 1950s,[1] and defines a replacement of normal squamous epithelium in the oesophagus by intestinal metaplasia.[2] Harmful exposure to the gastric refluxate is one of several proposed factors, which may facilitate metaplastic development. BO is a relatively common endoscopic finding in an estimated 6–10% of patients with reflux and 1–2% of the general population,[3,4,5] and has been identified as a pre-cancerous lesion accountable for more than 95% of oesophageal adenocarcinoma (OAC) cases.[6] However, with estimated OAC incidences between 0.1% and 0.5% per year the majority of patients will never develop OAC.[7,8,9] Great efforts have therefore been made to define high-risk patients, markers for progression to OAC and effective preventive measures.

In BO, the metaplastic cells have a higher proliferative rate than the normal squamous epithelium. It has been shown, that this activity increase during both persistent and pulsatile acid exposure via mitogen activated protein kinase pathways, transmitting growth regulatory signals in order to enhance proliferation and decrease apoptosis.[10,11] Inhibiting these pathways, by minimising acid-induced stimulation, might therefore be beneficial in preventing progression from BO to high-grade dysplasia (HGD) or OAC.

First line medical treatment is therefore acid inhibition with proton pump inhibitors (PPI's). Apart from relieving symptoms, inhibition of acid production should decrease the reflux of acid into the oesophagus, thereby decreasing the ongoing inflammation, proliferation and risk of dysplasia in the epithelia. Especially in BO patients, with most to gain from acid inhibition, this effect is desired.[8] The use of PPIs has risen rapidly – but so have the incidence of OAC.[12] Studies investigating the potential protective effects of PPI's on BO have found some or none protective effect from PPIs.[13,14,15,16,17,18,19] However, the majorities of published studies had methodological limitations, were limited in size and follow-up and relied on selected patient cohorts.

Further studies of whether the use and adherence of acid-inhibiting drugs would influence the risk of OAC and HGD among patients with BO are needed. To address this, we conducted a large cohort study in patients with BO to assess: (i) the potential effect of acid lowering drugs on the risk of developing OAC or HGD in BO; (ii) the effect of duration and/or adherence (intensity) of medication use.

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